The use of estradiol in estrogen replacement therapy is well known, and in fact an estradiol transdermal system comprising estradiol and ethanol gelled with hydroxypropyl cellulose in a reservoir-type transdermal patch is commercially available from CIBA Pharmaceutical Company (ESTRADERM.RTM.).
Various patents and published applications also relate to transdermal estradiol systems. For instance, U.K. patent application 2,093,694 discloses co-administration of estradiol and ethanol to increase dermal penetration of the drug. Several other publications relate in general to enhancing dermal penetration of drugs and also specifically name estradiol; U.S. Pat. No. 4,658,343 to Leeper et al discloses the use of polyethylene glycol monolaurate as a penetration enhancer; U.K. patent application 2,158,355 to Sarpotdar et al disclose the similar use of a combination of propylene glycol and glycerin in specified ratios; and European patent application 147,146 to Tsuk discloses menthol as a penetration enhancer.
Other patent publications discloses the use of a matrix or gel for transdermally delivery estradiol: PCT publication W087/07138 to Chien et al discloses estradiol microdispersed in a polymer (e.g. a silicone polymer) matrix; U.S. Pat. No. 4,668,232 to Cordes et al discloses a drug in a reservoir comprised of a polymer matrix composed of a rubber, an adhesive resin material, and a water-swellable polymer (e.g. a polysaccharide); U.S. Pat. No. 4,559,222 to Enscore et al discloses a mineral oil-polyisobutylene-colloidal silicon dioxide matrix useful for transdermal delivery of estradiol, among other drugs; German patent application 3,333,240 discloses estradiol dissolved in a gel, which gel is dispersed in a crosslinked silicone elastomer; French patent application 2,547,502 and U.S. Pat. No. 4,291,014 to Keith et al both disclose a transdermal matrix suitable for estradiol which comprises a polar plasticizer (e.g. polyethylene glycol), a polyvinyl alcohol and a polyvinyl pyrrolidone.
Still other patents relate to the more mechanical aspects of transdermal devices suitable for estradiol administration. European patent application 250,125 to Berry et al and U.K. patent application 2,185,187 to Campbell et al disclose drug-containing matrices incorporating fibers, which fibers absorb the active or impart flexibility to the device, respectively; U.S. Pat. No. 4,666,441 to Andriola et al discloses a transdermal device with multiple compartments to prevent uneven settling of the active in the patch when stored; and U.S. Pat. No. 4,624,665 to Nuwayser discloses microparticles of drug dispersed in a viscous material.
Effective transdermal administration of many drugs has been achieved using various skin penetration enhancers. Oleic acid has been reported to be a penetration enhancer; see Cooper, "Increased Skin Permeability for Lipophilic Molecules", J. Pharm. Sci., 73, 1153 (1984), wherein the use of varying concentrations of oleic acid in a polar solvent such as a diol (especially propylene glycol) enhanced the penetration of salicylic acid. U.S. Pat. No. 4,305,936 discloses a solution for topical or local application of a corticosteroid comprising a clyceral ester of a fatty acid of 6 to 22 carbon atoms, an alkanol cosolvent (e.g., dipropylene glycol), and a "suitable auxiliary adjuvant", e.g., oleic acid. PCT Application No. US86/02584 discloses enhanced penetration of mouse skin by estradiol in a carrier comprising 2-ethyl-1,3-hexane diol and oleic acid.
Disclosures relating to skin penetration enhancement with N-methyl-2-pyrrolidone (m-pyrol) include Bennett et al., "Optimization of bioavailability of topical steroids: non-occluded penetration enhancers under thermodynamic control", J. Pharm. Pharmacol., 37, 298 (1985), wherein both m-pyrol and a combination of oleic acid and propylene glycol were reported to increase steroid (betamethasone 17-benzoate) bioavailability. U.S. Pat. No. 4,557,934 to Cooper discloses a combination of Azone and m-pyrol or a C.sub.3 -C.sub.4 diol to enhance penetration of a variety of drugs, although estradiol is not specifically mentioned.